1. Field of the Invention
Isobutyramide is of interest as a therapeutic agent for sickle cell anemia (S. P. Perrine, D. V. Faller, Experientia 49 (1993) 133). The dose of the active substance required for therapy is extremely high. This is why the purity of this substance is required to be particularly high.
The preparation of isobutyramide and related amides has been described many times in the literature: Houben-Weyl, Methoden der Organischen Chemie. Volume VIII, pages 655 et seq., N.O.V. Sonntag, Chem. Revs. 52 (1953) 237.
2. Description of Related Art
The simplest method for preparing these amides is to react acid chlorides with aqueous ammonia: O. Aschan, Chem. Ber. 31 (1898) 2348, R. E. Kent, S. M. McElvain, Organic Synthesis, Coll. Vol. III, 490-492). However, the Aschan method provides low yields. Better yields are obtained by the Kent-McElvain process.
However, this process requires multistage isolation of the product. The purity achieved thereby does not meet clinical requirements.
Good yields are obtained in a non-aqueous process described by G. E. Philbrook (J. Org. Chem. 19 (1954) 623).
This entails dropwise addition of isobutyryl chloride to a solution of ammonia in benzene. Since the solubility of ammonia in benzene is only low, a stream of gaseous ammonia is passed through the solution throughout the addition time.
Attempts to simplify the process by introducing ammonia as gas or in liquid form into the acid chloride lead, according to G. E. Philbrook, to formation of large amounts of the diamide I. EQU (H.sub.3 C).sub.2 CH--CO--Cl+NH.sub.3 .fwdarw.(H.sub.3 C).sub.2 CH--CO--NH--CO--CH(CH.sub.3).sub.2
Traces of isobutyronitrile are formed in the preparation of isobutyramide. Removal of isobutyronitrile by distillation is difficult when the benzene is reused as solvent, so that this byproduct accumulates on repeated use of the benzene. However, the highly toxic nitrile must not be present even in the smallest traces in isobutyramide used for medicinal purposes.